Opioids are the most powerful analgesics commonly used in the clinical management of moderate to severe pain. Besides many known side effects of opioids, compelling evidence has accumulated over the last decade indicating that abnormal pain sensitivity such as hyperalgesia occurs in the absence of an overt naloxone-precipitated opioid withdrawal in animals receiving opioids. Moreover, a growing body of evidence suggests that the development of opioid-induced pain sensitivity (OIPS) is mediated through the neural and molecular mechanisms that interact with those underlying the development of pathological pain. Thus, the development of paradoxical OIPS may be contributory to clinical pain following a progressive opioid therapy, thereby adversely affecting the effectiveness of clinical opioid use. While clinical observations have indicated the possible presence of OIPS in pain patients on opioid therapy, a systematic investigation into this important issue has not yet been undertaken particularly in chronic non-malignant pain patients on opioid therapy. Specifically, a number of issues remain to be addressed: 1) Can OIPS be assessed clinically through descriptive and quantitative pain assessment tools such as measuring changes in pain threshold and identifying abnormal clinical pain characteristics? 2) Do various types and doses of opioids play a different role in the development of OIPS? 3) Can OIPS be differentiated from opioid tolerance in a clinical setting? And, 4) Can the adverse effects of OIPS on clinical opioid use be reduced through supervised opioid dose adjustment? In the proposed studies, we will use multidisciplinary approaches including quantitative sensory testing and pain inventory to accomplish two specific aims: 1) to examine the clinical features of OIPS in chronic non-malignant pain patients on opioid therapy, and 2) to explore clinical tools useful to diagnose OIPS and to reduce adverse effects of OIPS on opioid therapy. The data obtained from the proposed studies will provide insight into the relationship between the development of opioid-induced pain sensitivity and clinical opioid therapy and suggest new diagnostic and management tools to improve the effectiveness of clinical opioid use for chronic pain management.